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Targeting the mucosal immune system in a pregnant mouse model to prevent experimental allergic airways disease in the offspring

Mincham KT, Scott NM, Lauzon-Joset JF, Holt PG, Strickland DH.

Seminal studies of traditional farming families across Europe indicate that maternal exposure to benign environmental microbial stimuli whilst pregnant can potentially play a key role in mitigation of asthma risk in their offspring. The potential to harness this environmental phenomenon by therapeutically mimicking farm microbial exposure in pregnant women therefore represents a novel strategy for protection against the onset of allergic disease in children. In this pre-clinical study, we aim to investigate the therapeutic potential of a novel microbial derived immune stimulating agent (OM85) in protecting against the development of allergic asthma in offspring via treatment of the pregnant mother during gestation. We have so far shown that at baseline, ovalbumin sensitised and challenged female offspring have a significantly increased airways eosinophil population than their male counterparts. This finding is further reflected in an increased concentration of pro-inflammatory cytokines within the lungs of females. Importantly, we have also shown that sensitised female offspring from OM85 treated mothers have significantly attenuated airways eosinophilia after aerosol challenge. Multi-colour flow cytometry has enabled us to identify alterations within both regulatory T cell (Treg) and dendritic cell (DC) populations of the airways draining lymph nodes, parenchymal lung and trachea of 6-week old offspring. This preliminary data suggests maternal OM85 treatment has the capacity to modulate immunological mechanisms within the offspring that have previously been implicated in the pathogenesis of allergic airways disease. Furthermore, maternal OM85 treatment may have a differential impact on gender-associated disease outcomes. Future studies will investigate the underlying mechanisms promoting protection in the offspring. Fetal samples (fetal bone marrow, fetal liver, fetal thymus, fetal lung and placenta) collected at gestation day 18.5 will enable the identification of molecular signatures associated with maternal OM85 treatment. Fetal DNA will be used to determine fetal gender via PCR. After sex determination, female only tissue samples will undergo RNA-seq to identify molecular signatures within fetal tissue associated with maternal OM85 treatment during gestation. Maternal bone marrow will also undergo RNA-seq to assess the molecular impact of OM85 from a maternal perspective.

Plain language summary: Studies in Europe have shown that exposure of pregnant women to high levels of microbial products such as dust from farm barns, somehow stimulates the maturation of immune function maturation in their offspring, making them strongly resistant to development of asthma and allergies. We are trying to reproduce this finding experimentally in mice using a microbial derived product (OM85) which is used in Europe to boost resistance to infection. If this is successful, we will investigate the underlying protective mechanisms, with the long term aim of developing a new protective treatment for trialling in humans.